Tuberculosis

Bálint Beatrix MD, PhD

SZTE, Dpt. of Pulmonology

Deszk

2015.

Tuberculosis

TB a chronic bacterial infection, causes more deaths worldwide than any other infectious disease.

TB is spread through the air and usually infects the lungs, although other organs are sometimes involved.

Some 2 billion people - one-third of the world's population - are infected with the TB organism,

Tuberculosis kills 1.7 million people every year, and is the major killer of people living with HIV.

Mycobacterium tuberculosis.

History 1.

Germ theory: -Robert Koch (1882)-Pathogenicity of Mycobacterium tuberculosis -Konrad Röntgen (1892)- X ray

Paleopathological evidences- skeletal TB, bone TB

Ancient greek physisians used the word PHTYSIS 8th-9th century ¼ of the european adults died from TB.

TB in the World (number of TB cases)

Tbc incidencia Európában az elmúlt években

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TB in EUROPE

EpidemiologyRegion

Incidence

Prevalence

Deaths

Population

Africa2,300,00

02,500,000

220,000

857,382,000

Americas 260,000 330,000 21,000 943,019,000

Eastern Mediterranean 660,000 1,000,000 99,000 608,628,000

Europe 380,000 500,000 45,000 899,500,000

South-East Asia3,500,00

05,000,000

480,000

1,830,361,000

Western Pacific1,700,00

02,500,000

130,000

1,808,797,000

Global Total8,800,00

011,830,00

0995,0

006,947,687,0

00

TB and HIV

People living with HIV are from 26-31 times more likely to develop TB than persons without HIV. TB is the most common presenting illness among people living with HIV, including among those taking antiretroviral treatment and it is the major cause of HIV-related death.

WHO policy on collaborative TB/HIV activitiesGuidelines for national programmes and other stakeholdershttp://apps.who.int/iris/bitstream/10665/44789/1/9789241503006_eng.pdf?ua=1&ua=1

Mycobacterium tuberculosis

• The causative agents for tuberculosis

• Discovered by Robert Koch in 1882

• ~25 % of world’s population infected

• 25 million is infected in USA

Mycobacterium tuberculosis: Tbc-t okozó baktérium

Robert Koch 1882-ben fedezte fel

MicrobiologyMycobacterium tuberculosis: obligate, aerobic parazite, acid-fast

slow growth, visible colonial growth: 4-6 weeksINH resistant and sensitive strains are different

Direct examination: Ziehl-Neelsen stain:4 m long and 0,2-0,5 m wide10 000 organism/ml of sputumsmear positive

Culture of sputum/fluidM. tuberculosis: growths slowly, lack of pigment, produces

Niacin: M. bovis: niacine negativeDrug sensitivity test.

Blood test: Today's policy recommendation applies to blood tests for active TB. Blood tests for inactive TB infection (also known as dormant or latent TB) are currently under review by

WHO. The new recommendation comes after 12 months of rigorous analysis of evidence by WHO and global experts. Overwhelming evidence showed that the blood tests produced an unacceptable level of wrong results - false-positives or false-negatives - relative to tests endorsed by WHO.

Test Site Major Findings/results of Systematic review

Sputum smear microscopy

Pulmonary • fluorescence microscopy is on average 10% more sensitive than conventional microscopy. Specificity of both fluorescence and conventional microscopy is similar. Fluorescence microscopy is associated with improved time efficiency.•Same-day sputum smear microscopy is as accurate as standard smear Microscopy. Compared with the standard approach of examination of two smears with light microscopy over 2 days, examination of 2 smears taken on the same day had much the same sensitivity (64% for standard microscopy vs 63% for same-day microscopy) and specificity (98% vs 98%)

nucleic acid amplification tests (NAATs) [other than Xpert MTB/RIF]

Pulmonary and extra-pulmonary TB

Commercial, standardized NAATs have high specificity and positive predictive value, however, they have relatively lower (and highly variable) sensitivity and negative predictive value for all forms of TB, especially in smear-negative and extrapulmonary disease

WHO-approved microbiologic tests for tuberculosisDiagnosis of active TB 1.

Test Site Major Findings/results of Systematic review

Xpert MTB/RIF Pulmonary TB and extrapulmonary TB and RIF resistance

Xpert MTB/RIF used as an initial diagnostic test for detection of M. tuberculosis and rifampicin is sensitive and specific. Xpert MTB/RIF is also valuable as an add-on test following microscopy for patients who are smear-negative.an Xpert MTB/RIF result that is positive for rifampicin resistance should be carefully interpreted and take into consideration the risk of MDR TB in a given patient and the expected prevalence of MDR TB in a given setting.• when used as an initial test replacing smear microscopy Xpert MTB/RIF achieved a pooled sensitivity of 88% and pooled specificity of 98%.• for detection of rifampicin resistance Xpert MTB/RIF achieved a pooled sensitivity of 94% and pooled specificity of 98%

Automated liquid cultures and rapid MPt64-based species identification tests

Pulmonary TB and extrapulm. TB specification

automated liquid cultures are more sensitive than solid cultures; time to detection is more rapid than solid cultures.• mPT64-based rapid immunochromatographic tests (ICT) for species identification has high sensitivity and specificity

WHO-approved microbiologic tests for tuberculosis Diagnosis of active TB 2.

The Xpert MTB/RIF is an automated, cartridge-based nucleic amplification assay for the simultaneous detection of TB and rifampicin resistance directly from sputum in under two hours. It can identify Mycobacterium tuberculosis (MTB) DNA and resistance to rifampicin (RIF) by nucleic acid amplification technique (NAAT). In 2010, the WHO endorsed it for use in TB endemic countries and declared it a major milestone for global TB diagnosis.

Atípusos Mycobacterium identifikálására is alkalmas.

Budapest OKTPI/ Corden Laboratóriumban elérhető

Mode of spread

• TB is spread from in microscopic droplets person to person — droplet nuclei — expelled from the lungs when a TB sufferer coughs, sneezes, speaks, sings, or laughs. Only people with active disease are contagious.

• People are most likely to be contagious when their sputum contains bacilli, when they cough frequently and when the extent of their lung disease, as revealed by a chest x-ray, is great.

* People who have been treated with appropriate drugs for at

least two weeks usually are not infectious.

Predisposing Factors• Babies and young children

• HIV infection

• substance abuse

• diabetes mellitus

• silicosis

• cancer

• leukemia or Hodgkin's disease

• severe kidney disease

• low body weight

• certain medical treatments – corticosteroid treatment

– organ transplants

– chemotherapy

How Tuberculosis Affects The BodyCOMMON SYMPTOMS

Fever

Coughing up blood or sputum

Weakness or fatigue

No appetiteWeight loss

A bad cough that lastsmore than three weeks

TB is spread when you inhale the bacteria in droplets expelled then

someone infected speaks or coughs.

Pain in the chest

COURSE OF INFECTION

INFECTION Can turn into either latent or active TB.

LATENT TB In the initial stage of disease, called latent TB, TB bacteria remain alive, but cannot spread to other tissue or people. Most infections will never get past this stage. 10 % of latent TB infections become active.

ACTIVE TB DEATHActive pulmonary TB Without treatment,

(TB in the lungs) is contagious. people who are HIV-negative have a mean 10-year fatality rate of 70 %

RECOVERYA full course of TB treatment takes6 to 9 months of taking several drugs.

Sources: CDC, PLoS One, WHO

Sources: CDC, PLoS One, WHO

HOW DOES TB DISEASE DEVELOP? There are two possible ways a person can become sick with TB

disease:

1.A person who may have been infected with TB for years and has been perfectly healthy. The time may come when this person suffers a change in health. The cause may be another disease like AIDS or diabetes. Or it may be drug or alcohol abuse or a lack of health care because of homelessness. Whatever the cause, when the body's ability to protect itself is damaged, the TB infection can become TB disease. In this way, a person may become sick with TB disease months or even years after they first breathed in the TB germs.

2. A person first breathes in the TB germs the body is unable to protect itself against the disease. The germs then develop into active TB disease within weeks. (This way TB disease develops happens much more quickly.)

Symptoms

Early TB (single or multiple nodule, caseous lesion)- no symptomes

Progresszive TB (cavitation, pneumonitis)- nonspecific symptomes: anorexia, fatigue, weight loss,

remittent fever, night sweets

- cough, sputum (mucopurulent)- haemoptysis- chest pain (inflammation of parietal pleura)

Laboratory findings

IIn advanced TB!

- RBC - Se albumin - WBC - Sodium - Calcium

Characteristic X-ray findings

• Apical, subapical patchy infiltration• Bilateral upper lobe infiltration• Dissemination: miliary tb• Lower lobe TB

– cavitation or infiltration– atelectesis, mass leasions, large cavitation with fluid, pneumonic-like infiltration

• Non-specific• Pleural effusion• Special

– Simon foci: The initial infection leaves nodular scars in the apices of one or both lungs, called which are the most common seeds for later active TB.

– Ghon foci: calcified scars of primary infection and residual calcified hilar lymph nodes.

Tbc: tuberculoma

Tb pneumonia

Ghon komplex

Tb hilar adenopathy

Miliary tb

Tb: miliary

Tb: cavity

Tb: cavity

Tb: cavity

Tb:progressive

Callus pleurae, residuum

Diagnosis• X-ray findings• Sputum/bronchoscopic lavage fluid smear + Negatíve tuberculin test: can not exclude the infection• Histology: TUBERCULOMA

• epitheloid cells, •Langhans giant cells, •lymphocytes, •caseous lesion (necrosis)

•Definitive diagnosis- culture- specification of the organism

Extrapulmonary TB (TB can involve any organ)

-TB of the tonsils, lymph nodes, abdominal organs, bones, and joints caused by ingestion of milk infected with M. bovis. (slaughtering cows with milk)

*GENITOURINARY TUBERCULOSIS

-kidney pyelonephritis. (chronic, "sterile" routine culture-negative)

-epididymis or prostate gland, baldder, vesicles.

-Salpingo-oophoritis

* TUBERCULOUS MENINGITIS (TB to the subarachnoid space)

* MILIARY TUBERCULOSIS (Generalized Hematogenous or Lymphohematogenous TB) Bone marrow involvement

* TUBERCULOUS PERITONITIS

*TUBERCULOUS PERICARDITIS

*TUBERCULOUS LYMPHADENITIS

*TUBERCULOSIS OF BONES AND JOINTS (Pott's disease)

*TUBERCULOSIS OF THE LIVER

Resistant TB 1.

Drug resistant tb: resistant to one of the anti-TB drugs.

Multi-drug-resistant tuberculosis (MDR-TB): resistant to at least isonicid(INH) and rifampicin (RMP), the 2 most powerful first-line treatment anti-TB drugs. The reasons why multidrug resistance continues to emerge and spread are mismanagement of TB treatment and person-to-person transmission.

-treatable TB when the course of antibiotics is interrupted and the levels of drug in the body are insufficient to kill 100% of bacteria. (Patients may feel better and halt their antibiotic course, drug supplies may run out or become scarce, patients may forget to take their medication from time to time or patients do not receive effective therapy.)

-MDR-TB is spread from person to person.

Resistant TB 2.

Extensively drug resistant tb (XDR-TB). is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin).

MDR-TB and XDR-TB both take substantially longer to treat than ordinary (drug-susceptible) TB, and require the use of second-line anti-TB drugs, which are more expensive and have more side-effects than the first-line drugs used for drug-susceptible TB.

In 2014, an estimated 480 000 people worldwide developed MDR-TB. It is estimated that about 9.7% of these cases were XDR-TB.

Prevention of MDR TB

• There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:– Rapid diagnosis & treatment– Completion of treatment: Previous treatment of TB is an indicator of

MDR TB. If the patient does not complete his/her antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. Also, drugs that are of poor quality or less in quantity, contribute to MDR TB.

– Patients with HIV/AIDS should be identified and diagnosed as soon as possible. They have great risk of developing drug resistance.

– Identify contacts who could have contracted TB: i.e. family members, people in close contact, etc.

– Research: Much research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB.

History of chemotherapy

Streptomycin 1946-1952ToxicityResistancyRecidive infection

Isonicid 1952-1970INH + PAS + StreptomycinTreatment-18 months

Rifampicin 1970RMP + INH 9 months RMP + INH + ETB 6 months

Therapeutic agents for tb• First line therapy• Isoniazid• Rifampin• Pyrazinamide• Streptomycin• Ethambutol

• Secund line therapy• Ethionamide• Cycloserine• Aminoglycosides• Capreomycin• PAS• Thiocetazone• Imipenem• Ampicillin• Metronidazole• Ciprofloxacin• Ofloxacin

Characteristics of 2nd line drugs

• Less effective drugs

• Poor GI tolarence

• Significant side effect profile

• Not well studied

• Some not readily available (PAS)

TreatmentAll patients who have not been treated previously and do not have other risk factors for drug resistance should receive a WHO-approved first-line treatment regimen using quality assured drugs. The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol.The continuation phase should consist of isoniazid and rifampicin given for 4 months. The doses of antituberculosis drugs used should conform to WHO recommendations. Fixed-dose combination drugs may provide a more convenient form of drug administration.

The principles of therapy

• Combination therapy – kills more effectively– Shortens therapy

• Prevents emergence of resistance:– INH/RAMP EMB SM PZA

• Treatment must be for a least six month• Bactericidal phase: 1 month• Strerilizing phase: months 3 through 6• Never add a single drug

Initial therapy: four drugs

• Isoniazid (INH) 300 mg daily

• Rifampin (RIF) 600 mg daily

• Pyrazinamide (PZA)25-30 mg daily

• Ethambutol (EMB)25 mg initially

Therapeutic Regimens

• Daily therapy• 6 months• Daily treatment• 180 doses• 2-3 % relapse

• Short course• 6 months• Twice or three times

weekly• 52-114 doses• Equivalent relapse

Preventive therapy for tuberculous infection

• Infection vs. active disease• Lifetime risk for active disease

– Higher in children– 10 % per year in HIV infected patients

• Mantoux skin test is the indicator of infection• Preventive therapy requires 6 months of

single drug therapy• Isoniazid

Therapy of MDR/XDR TB

• Patients with or highly likely to have tuberculosis caused by drug-resistant (especially MDR/XDR) organisms should be treated with specialized regimens containing quality-assured second-line antituberculosis drugs.

• The regimen chosen may be standardized or based on presumed or confirmed drug susceptibility patterns.

• At least five drugs, pyrazinamide and four drugs to which the organisms are known or presumed to be susceptible, including an injectable agent, should be used in a 6–8 month intensive phase, and at least 3 drugs to which the organisms are known or presumed to be susceptible, should be used in the continuation phase.

• Treatment should be given for at least 18–24 months beyond culture conversion.

TB and HIV 1.

People living with HIV are from 26-31 times more likely to develop TB than persons without HIV. TB is the most common presenting illness among people living with HIV, including among those taking antiretroviral treatment and it is the major cause of HIV-related death.

WHO-recommended collaborative TB/HIV activitieshttp://apps.who.int/iris/bitstream/10665/44789/1/9789241503006_eng.pdf?ua=1&ua=1

Tuberculosis Care with TB-HIV Co-management INTEGRATED MANAGEMENT OF ADOLESCENT AND ADULT ILLNESS (IMAI)http://www.who.int/hiv/pub/imai/TB_HIVModule23.05.07.pdf

TB and HIV 2.

TB and HIV co-infection is when people have both HIV infection, and also either latent or active TB disease. When someone has both HIV and TB, each disease speeds up the progress of the other. In addition to HIV infection speeding up the progression from latent to active TB, TB bacteria also accelerate the progress of HIV infection.

In 2013 of the estimated 9 million people who developed TB an estimated 1.1 million (13%) were HIV positive. There were also in 2013 360,000 deaths from HIV associated TB equivalent to 25% of all TB deaths, and around 25% of the estimated 1.5 million deaths from HIV/AIDS.2

HIV infection and infection with TB bacteria are though completely different infectionshttp://www.tbfacts.org/tb-hiv/#sthash.aoiSFij9.dpuf

Nontuberculous mycobacteria

• Pumonary disease– M. avium, kansasii, abscessus, xenopi,

malmoense

• Lymphadenitis– M. avium, scrofulaceum, malmoense

• Cutaneous disease– M. marinum, fortuitum, chelonea, ulcerans

• Disseminated disease– M. avium, kansasii,chelonea, haemophilum

Treatment of nontuberculous mycobacteria

• The antituberculotic drugs are usually not effective

• M. kansasii: INH, RIF, EMB

• M. avium: macrolide, Rifamycin, EMB

• Rapid growers: clarithromycin and 2nd agents

History 2.

Outstanding representatives of the arts and political life who suffered from TB

• Balzac• Brontë sisters• Chekov• Chopin• Dostoevsky• Kafka• D.H. Lawrence• Sir Walter Scott

• E. A. Poe• Voltaire• John Keats• Rembrandt’s wife

(Sashka) and his son (Titus)

• Marquise de Pompadur

• Napoleon II

Literature• International standards For Tuberculosis Care 3rd edition,

2014. http://www.who.int/tb/publications/ISTC_3rdEd.pdf• http://intranet.tdmu.edu.ua/data/kafedra/internal/

propedeutic_vn_des/classes_stud/en/med/lik/ptn/Phtisiology/4/Lesson_05_%20%20secondary%20tub%2014.1.htm

• http://www.who.int/features/qa/79/en/• http://www.who.int/tb/challenges/en/• http://apps.who.int/iris/bitstream/

10665/44789/1/9789241503006_eng.pdf?ua=1&ua=1

Model: Simonetta Catanea died of TB at the age of 23.Symptomes:whitish-pink colour of skin, small shoulders,

narrow thorax, low-placed and close breastssigns of phtisis