Tuberculosis Blint Beatrix MD Ph D SZTE Dpt

Tuberculosis Bálint Beatrix MD, Ph. D SZTE, Dpt. of Pulmonology Deszk 2018. 11. 08

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. Paleopathological evidences - skeletal TB, bone TB Ancient greek physisians used the word PHTYSIS 8 th-9 th century ¼ of the european adults died from TB. Germ theory: -Robert Koch (1882)-Pathogenicity of Mycobacterium tuberculosis -Konrad Röntgen (1892)- X ray

TB in the World

TB in EUROPE

Epidemiology Region Africa Incidence 2, 300, 000 Prevalence Deaths 2, 500, 000 220, 000 Population 857, 382, 000 Americas 260, 000 330, 000 21, 000 943, 019, 000 Eastern Mediterranean 660, 000 1, 000 99, 000 608, 628, 000 Europe 380, 000 500, 000 45, 000 899, 500, 000 South-East Asia 3, 500, 000 5, 000 480, 000 1, 830, 361, 000 Western Pacific 1, 700, 000 2, 500, 000 130, 000 1, 808, 797, 000 Global Total 8, 800, 000 11, 830, 000 995, 000 6, 947, 687, 000

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

Microbiology Mycobacterium tuberculosis: obligate, aerobic parazite, acid-fast slow growth, visible colonial growth: 4 -6 weeks INH resistant and sensitive strains are different Direct examination: Ziehl-Neelsen stain: 4 m long and 0, 2 -0, 5 m wide 10 000 organism/ml of sputum smear positive Culture of sputum/fluid M. tuberculosis: growths slowly, lack of pigment, produces Niacin: M. bovis: niacine negative Drug 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.

WHO-approved microbiologic tests for tuberculosis Diagnosis of active TB 1. Test Site Major Findings/results of Systematic review Sputum smear microscopy Pulmonary • fluorescence microscopy is on average 10% more nucleic acid amplification tests (NAATs) [other than Xpert MTB/RIF] Pulmonary and extrapulmonary TB 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%) 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 smearnegative and extrapulmonary disease

WHO-approved microbiologic tests for tuberculosis Diagnosis of active TB 2. 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 smearnegative. 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 MPt 64 -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. • m. PT 64 -based rapid immunochromatographic tests (ICT) for species identification has high sensitivity and specificity

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.

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

COURSE OF 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 Active pulmonary TB (TB in the lungs) is contagious. DEATH Without treatment, people who are HIV-negative have a mean 10 -year fatality rate of 70 % RECOVERY Sources: CDC, PLo. S One, A full course of TB treatment takes 6 to 9 months of taking several drugs. 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

-*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

Laryngitis tuberculosa Constrictive Pericarditis. CT of chest: markedly thick pericardial calcification around the heart from patient with history of tb pericarditis

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 sideeffects 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.

2007

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.

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 2 nd line drugs • • • Less effective drugs Poor GI tolarence Significant side effect profile Not well studied Some not readily available (PAS)

Treatment All 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 (4 -5) – kills more effectively – Shortens therapy • Prevents emergence of resistance: – INH/RAMP EMB SM PZA • • Treatment must be for at 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 drugresistant (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 2631 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 activities http: //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_HIVModule 23. 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 infections http: //www. tbfacts. org/tb-hiv/#sthash. aoi. SFij 9. 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 2 nd 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

References • International standards For Tuberculosis Care 3 rd edition, 2014. http: //www. who. int/tb/publications/ISTC_3 rd. Ed. pdf • http: //intranet. tdmu. edu. ua/data/kafedra/internal/proped eutic_vn_des/classes_stud/en/med/lik/ptn/Phtisiology/4 /Lesson_05_%20%20 secondary%20 tub%2014. 1. htm • http: //www. who. int/features/qa/79/en/ • http: //www. who. int/tb/challenges/en/ • http: //apps. who. int/iris/bitstream/10665/44789/1/97892 41503006_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 breasts signs of phtisis